8/14/2019 Abstract: Lead Optimization and Drug Metabolism and Pharmacokinetics(DMPK) Has Become

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Lead Optimization in Drug Discovery/DMPK:ase Study Hepatitis C virus Protease Inhibitor SCH503034

Abstract: ( )Lead Optimization and drug metabolism and pharmacokinetics DMPK has become primary. ,focuses of research involved in drug discovery Using in vivo and in vitro DMPK screening a

large array of compounds during LO process has resulted in development of compounds that have.acceptable DMPK properties In this poster I present a general drug discovery process and a

.case study using HCV protease inhibitor as an example

Introduction:Multifaceted Operation ,Involves interaction between DMPK scientist

.biologist and physical chemistsGoal: to find molecule with desired

,Biological Activity DMPK property and safety

Lead Generation as a part of new drug

discovery:Contemporary parallel and combinatorial

chemical synthesis produce large arrays ofcompoundsImprovements by structural chemist using

, . . - ,variety of tools e g X ray crystallographyHigh throughput binding targets

New automated in vitro Screening can test .100 s of sample in short time

Increase our ability to create New Chemical( )Entity NCE

Drug Metabolism As a Part of New DrugDiscovery:

Scheme shows: Nature oflead optimization leading

to candidateDMPK provides with tools

and the assay to assessvarious NCE in terms of

ADME and pharmacokineticparametersGoal is to find a

compound suitable fordevelopment

Case study: HCV protease Screening Paradigm:epatitis C virus :ethod~

170 million people infected withHCVChronic form of hepatitisHCV servers a template for cap

independent translation through its .5 terminal -3000amino acid undergo co and post

translational proteolytic maturation.by host and virus

Virus encoded protease located at

.NS3 -This effect targeting the E Sbinding site resulted in CH 503034

DMPK screening :DMPK screening applied to

HCV compound ~ METHOD , ---10 000compounds Repliconassay ,1 000 met the criterion of

.IC901st level--- Screening with

, ,Caco2 CYP enzyme inhibition

liver uptake screening2nd level---More labor

,intensive assay studies inrodent and non rodent.species

,Out of 1000 3 were advancedleads with SCH503034

Result-moderate oral bioavailability in rats and dogsAbsence of reactive metabolite > , ,IC50 5uM for CYPs3A4 2D6 2C8 and 2C9Moderate huan Hepatocyte clearanceNo CYP induction liability

Macrocyclic Compounds: SCH,416538 resistance to peptidases

, .and amidases Better potencySecondary Amides: SCH

, ,446211 reasonable half life.potential dosage regimen

Primary Ketoamides: SCH 503034met criteria for this program and

.was advanced into development

Conclusion: DMPK screens and new techniques have

.become an essential part of drug discovery processThere is continuous need to improve predictions by.using in vitro evaluations

Future: It may become possible to use in silico DMPKcomputer model parameters to support the rapidscreening of drugs to shorten the time frame of lead

.optimization

Reference: .- . , . , .K C Cheng1 Walter A Korfmacher1 Ronald E White1

.and F George Njoroge2.1Department of Drug Metabolism and Pharmacokinetics

-2Chemistry Department Schering Plough, ,Research Institute 2015 Galloping Hill Road

, .Kenilworth NJ 07033 USA

Lead optimization in a DMPK environmentProperty Definition/Requirement

Potency The intrinsic ability of a compound to produce a desirablepharmacological response (usually measured via high throughput in vitroscreens)

Oral Bioavailability The ability of a compound to pass through multiples barriers, such as theGI tract and the liver in order to reach the target

Duration (Half-life) The ability of the compound to remain in circulation (or at the target site)for sufficient time to provide a meaningful pharmacological response

Safety The compound has sufficient selectivity for the targeted response relativeto non-targeted responses so that an adequate therapeutic index exists

Pharmaceutical Acceptability The compound has suitable pharmaceutical properties, such as areasonable synthetic pathway, adequate aqueous solubility, reasonable rateof dissolution, good chemical stability, etc.

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A few advanced leads were identified that had.acceptable DMPK characteristics

It went through a DMPK profiling process for thefinal selection of the best compound for drugdevelopment (3rd level).